# Project 1: Development of pharmacologic strategies to degrade mutant EGFR.

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $287,962

## Abstract

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are detected
in 10-15% of Caucasian and 30-40% of Asian patients with non-small cell lung cancer (NSCLC). EGFR
tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib and afatinib, are the standard of care initial
treatment for patients with advanced EGFR mutant lung cancer. Although the vast majority of patients have
significant tumor reductions with EGFR inhibitor treatment, acquired drug resistance inevitably develops in the
majority of patients. For the most common mechanism of acquired resistance, EGFR T790M, detected in 60%
of patients, osimertinib (AZD9291), a chemically diverse (pyrimidine; gefitinib, erlotinib and afatinib are
quinazolines) mutant selective covalent EGFR inhibitor, is clinically effective in >60% of patients and has
recently been approved for clinical use in the United States, Europe and Japan.
However, resistance mechanisms to mutant selective EGFR inhibitors have already begun to be identified both
in preclinical models and from patients. These include EGFR C797S, the site of covalent binding of osimertinib,
which we identified by sequencing of plasma DNA from patients who relapsed on osimertinib treatment.
Remarkably, EGFR mutations that cause resistance to osimertinib retain sensitivity to quinazoline based
EGFR inhibitors including gefitinib when present in the absence of EGFR T790M. In contrast cancers with
three EGFR mutations (EGFR activating mutation, EGFR T790M and EGFR C797S) are resistant to all current
EGFR inhibitors. In collaboration with Michael Eck (Core B; structure), we have recently identified and studied
a novel mutant selective allosteric EGFR inhibitor (EAI045). In conjunction with cetuximab EAI045 is effective
both in vitro and in vivo in EGFR mutant models harboring C797S suggesting that novel drug development
approaches can identify unique strategies to inhibiting mutant EGFR even in the presence of multiple drug
resistance mutations to EGFR TKIs.
The current clinical paradigm is to treat EGFR mutant lung cancer patients with successive single agent EGFR
TKIs. Our recent preclinical studies, however, demonstrate that osimeritinib and gefitinib can overcome non-
overlapping EGFR mediated drug resistance mutations, suggesting that dual EGFR inhibition with both agents
may be a more effective strategy. In the current proposal we will evaluate and develop new strategies,
specifically mutant selective EGFR specific degraders, determine whether such approaches, alone or in
combination with existing ATP competitive EGFR inhibitors, overcome and/or more effectively limit the
emergence of drug resistance than successive single agent treatments.

## Key facts

- **NIH application ID:** 10003958
- **Project number:** 5P01CA154303-09
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Pasi A Janne
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $287,962
- **Award type:** 5
- **Project period:** 2012-05-11 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003958

## Citation

> US National Institutes of Health, RePORTER application 10003958, Project 1: Development of pharmacologic strategies to degrade mutant EGFR. (5P01CA154303-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10003958. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*